Only a small minority of people who fall victim to a violent attack or witness a bloody accident suffer the recurring nightmares, hypervigilance, and other symptoms of posttraumatic stress disorder (PTSD). Women seem to be twice as susceptible as men, but otherwise researchers know virtually nothing about who is most at risk or why. Now a study has linked a genetic mutation and blood levels of a particular peptide—a compound made from a short string of the same building blocks that make up proteins—to the severity of PTSD symptoms in women. The finding could lead to tests to identify people who may need extra help after a traumatic event.
In the new study, researchers led by Kerry Ressler, a psychiatrist and molecular neurobiologist at Emory University in Atlanta, focused on a peptide thought to play a role in cells' response to stress: pituitary adenylate cyclase-activating polypeptide (PACAP). The team measured levels of PACAP in the blood of 64 patients who volunteered for their study at Grady Memorial Hospital in Atlanta. The vast majority of volunteers were from poor neighborhoods in the city, and Ressler says more than 90% reported having witnessed or suffered from a traumatic event such as gun violence or physical or sexual assault in the past.
The researchers found a correlation between PACAP levels and scores on a standard scale of PTSD symptoms in women—but no such correlation in men. In a second group of 74 women, the researchers found a similar correlation between PACAP levels and symptom severity. Ressler estimates that with all else being equal, women with high PACAP levels are up to five times as likely as women with low levels to have symptoms severe enough to meet the diagnostic criteria for PTSD.
The team also found a genetic link to PTSD. In a study with 1200 patients from the same hospital, the researchers found that a variation in the gene encoding the receptor for PACAP correlates with more severe symptoms in women—but not in men. Ressler estimates that women with the variation have up to twice the risk of developing PTSD after a traumatic event. All in all, the findings, published online today in Nature, suggest that PACAP and its receptor play an important role in determining PTSD susceptibility in women.
But why only in women? Ressler hypothesizes that estrogen, the primary female sex hormone, may amplify the effects of stress. The gene for the PACAP receptor can be turned on and off by estrogen. And the genetic variation his group identified lies within one of the sites in the PACAP receptor gene that is specifically sensitive to estrogen and may alter the way estrogen regulates the gene's activity.
The findings don't have immediate practical applications, but Ressler says they might one day lead to tests that could help determine who's at greatest risk of developing PTSD. Such tests might help emergency doctors identify patients who would benefit most from intensive psychological therapy in the weeks following a car accident or other traumatic event, Ressler says.
"One could hardly ask for a better story," says Ahmad Hariri, a neuroscientist who studies the biology of anxiety at Duke University in Durham, North Carolina. The next steps will be to investigate how the genetic variant Ressler's group identified affects gene expression, how traumatic experiences affect PACAP activity, and whether this pathway also has a role in other types of anxiety disorders, Hariri says. "The research is certain to generate a rush of interest in pursuing this pathway for better understanding the biology of stress and developing novel targets for the treatment and possibly prevention of stress-related disorders."